Inhibitors of the DNA repair enzyme AAG

DNA, the genetic blueprint of life, is targeted by a multitude of damaging species of both internal and external origin. This damage can result in the loss of genomic integrity and increase susceptibility to immunodeficiency, neurological disorders, and cancers. Sophisticated DNA repair mechanisms, such as base excision repair, have evolved to correct the damaged DNA and restore genomic integrity. However, errors within these repair mechanisms can result in mutagenic events. Base excision repair, initiates via the use of a DNA glycosylase. Overactivity of alkyladenine glycosylase (AAG), an example of a DNA glycosylase, can result in accumulation of toxic abasic sites that result in mutagenic events and cause cell death. The design and synthesis of a highly active inhibitor of AAG is required. Herein, the rationale behind the design of azanucleoside mimics of such an inhibitor is described, followed by their synthesis. Additionally, development, optimisation, and application of an AAG inhibitory bioassay will provide some of the key structural activity relationships to allow determination of the feasibility of using these inhibitors as therapeutic agents.